Process Development for the Manufacture of a Topical Pan-Trk Inhibitor Incorporating Decarboxylative sp2–sp3 Cross-Coupling

IF 3.1 3区化学 Q2 CHEMISTRY, APPLIED Organic Process Research & Development Pub Date : 2024-11-12 DOI:10.1021/acs.oprd.4c00325

Michael S. Ashwood, Edward I. Balmond, David Fengas, Jane McGuffog, Jonathan Moore, Nicola M. Robas, Neil G. Stevenson, Lisa Wise

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Abstract

The development of a synthetic route toward topical pan-Trk inhibitor 1 is described as an eight-stage synthesis from available starting materials. Process improvements include the development of a decarboxylative sp²–sp³ cross-coupling which had not previously been demonstrated on scale. Parameters were explored, balancing the safety aspects with conversion and selectivity, scaling up in a stepwise fashion to multiple successful 0.7 kg batches. The cross-coupling showed high diastereoselectivity, with the opposite diastereomer not observed in the crude ¹⁹F NMR. Selectivity was further improved by crystallizing the downstream pyrrolidine salt after Boc deprotection, to give a diastereomer ratio of 99.5:0.5 by UPLC. This route has been reproducibly demonstrated in two GMP campaigns delivering API on kilogram scale, in >98% area purity by HPLC. The route design, solid-form screening, process research, and manufacture have enabled crucial first-in-human (FIH) clinical studies, through focus on speed of delivery.

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结合脱羧sp2-sp3交叉偶联的局部Pan-Trk抑制剂的生产工艺开发

本文介绍了从现有起始原料出发，经过八个阶段合成出局部泛 Trk 抑制剂 1 的合成路线。工艺改进包括开发出一种脱羧 sp2-sp3 交叉偶联方法，这种方法以前从未大规模应用过。在平衡安全性、转化率和选择性的基础上，对参数进行了探索，并逐步扩大到多个 0.7 公斤的成功批量。交叉偶联显示出很高的非对映选择性，在粗 19F NMR 中没有观察到相反的非对映异构体。通过对 Boc 去保护后的下游吡咯烷盐进行结晶，进一步提高了选择性，经 UPLC 测定，非对映异构体的比例为 99.5:0.5。在两次 GMP 生产活动中，该制备方法均得到了验证，原料药的产量达到了公斤级，HPLC 检测的面积纯度为 98%。通过路线设计、固体形式筛选、工艺研究和生产，并通过对交付速度的关注，实现了至关重要的首次人体 (FIH) 临床研究。

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来源期刊

Organic Process Research & Development 化学-应用化学

CiteScore

6.90

自引率

14.70%

发文量

251

审稿时长

2 months

期刊介绍： The journal Organic Process Research & Development serves as a communication tool between industrial chemists and chemists working in universities and research institutes. As such, it reports original work from the broad field of industrial process chemistry but also presents academic results that are relevant, or potentially relevant, to industrial applications. Process chemistry is the science that enables the safe, environmentally benign and ultimately economical manufacturing of organic compounds that are required in larger amounts to help address the needs of society. Consequently, the Journal encompasses every aspect of organic chemistry, including all aspects of catalysis, synthetic methodology development and synthetic strategy exploration, but also includes aspects from analytical and solid-state chemistry and chemical engineering, such as work-up tools，process safety, or flow-chemistry. The goal of development and optimization of chemical reactions and processes is their transfer to a larger scale; original work describing such studies and the actual implementation on scale is highly relevant to the journal. However, studies on new developments from either industry, research institutes or academia that have not yet been demonstrated on scale, but where an industrial utility can be expected and where the study has addressed important prerequisites for a scale-up and has given confidence into the reliability and practicality of the chemistry, also serve the mission of OPR&D as a communication tool between the different contributors to the field.